Sex hormones decrease inflammation triggered by anti-SARS-CoV-2 IgG in macrophages

Medical News: As the COVID-19 pandemic has affected millions globally, new insights into why certain groups experience severe illness have emerged. Researchers from the Amsterdam University Medical Center in the Netherlands have uncovered a crucial link between sex hormones - testosterone and estradiol - and the body’s inflammatory response to COVID-19. This Medical News report dives into their findings, which show that these hormones can reduce inflammation caused by the immune response to the virus, potentially offering protection to younger individuals while explaining why older men and women are more vulnerable.


Macrophages of male and female donors do not show statistically significant differences in cytokine production in the absence of sex hormones. (A) Schematic overview of the experimental setup. Human alveolar macrophage-like monocyte-derived macrophages were generated by differentiating peripheral monocytes with M-CSF and IL-10. The generated macrophages were then stimulated with viral stimulus poly(I:C) and/or immune complexes. Immune complexes were formed by plate-bounded SARS-CoV-2 spike proteins and monoclonal anti-spike IgGs. All conditions contained SARS-CoV-2 spike proteins. (B) Representative example of TNF production of macrophages upon stimulation with spike protein, poly(I:C), anti-spike IgG immune complexes, and combinations. (C) Data of multiple donors, in which cells were stimulated with spike and poly(I:C) in the or of anti-spike IgG. Data were analyzed with a paired t-test. (D) Macrophages of male and female donors do not produce statistically significant levels of TNF upon stimulation in the absence of exogenous sex hormones.
 
The Role of Sex Hormones in Immune Response
COVID-19 has been particularly severe for elderly individuals, obese people, and men, leading scientists to investigate the factors contributing to this heightened risk. Testosterone and estradiol, both of which decrease as people age, have caught researchers’ attention for their role in modulating immune responses. Previous studies showed that hyperinflammation in severe COVID-19 cases is often triggered by anti-spike IgG antibodies that activate alveolar macrophages in the lungs. The study explores how these hormones interact with the immune system, particularly with macrophages.
 
The research team, including experts from the Center for Experimental and Molecular Medicine and the Medical Microbiology and Infection Prevention departments at Amsterdam University Medical Center, developed an in vitro model to test the effects of sex hormones on human macrophages exposed to viral stimuli and anti-spike IgG immune complexes. Their results were promising.
 
Key Findings: Testosterone Reduces Inflammation
Testosterone, often associated with male characteristics, also plays a role in reducing the body’s inflammatory response. The researchers tested different levels of testosterone, including concentrations typical of young adults, and found that testosterone significantly reduced the production of pro-inflammatory cytokines like TNF and IFN-γ in macrophages. These cytokines are part of the so -called "cytokine storm" that leads to severe complications in COVID-19 patients.
Interestingly, the reduction in inflammation occurred primarily when the macrophages were exposed to immune complexes formed by anti-spike IgG antibodies, rather than direct viral stimulation alone. This suggests that testosterone might have a specific role in controlling the immune system’s overreaction to the virus, especially in the later stages of infection when antibodies are more abundant.
 
The research also found that the beneficial effects of testosterone were present in both male and female cells. In addition, the hormone's ability to reduce inflammation did not diminish with age, meaning it could potentially benefit people of all ages. However, the study noted that individuals with low testosterone levels, such as older men and those with obesity, may miss out on this protective mechanism, contributing to their increased risk of severe COVID-19.
 
Estradiol’s Broad Impact on Reducing Inflammation
While testosterone played a key role in reducing specific inflammatory cytokines, estradiol - commonly associated with female biology - showed even broader effects. Estradiol reduced the production of a wide range of cytokines, including TNF, IL-1β, IL-6, and IFN-γ, which are all involved in the body’s inflammatory response to COVID-19. This hormone also affected both male and female cells, further supporting the idea that sex hormones could offer general protective benefits against inflammation.
 
Estradiol’s effects were consistent across different concentrations, with the researchers testing levels similar to those found in premenopausal women. These findings may help explain why premenopausal women tend to experience less severe COVID-19 symptoms compared to men of the same age or postmenopausal women. As estradiol levels decrease significantly after menopause, women lose this hormonal protection, potentially increasing their risk of severe illness.
 
How Sex Hormones Affect Immune Receptors
The researchers also explored how testosterone and estradiol affect the receptors on macrophages responsible for mediating inflammation. Specifically, they found that both hormones reduced the expression of Fc gamma receptors IIa and III (FcγRIIa and FcγRIII), which are critical for the inflammatory response triggered by anti-spike IgG immune complexes.
 
By reducing the expression of these receptors, testosterone and estradiol dampened the macrophages’ inflammatory response, potentially preventing the overreaction that leads to severe COVID-19. This discovery is particularly important because it offers a possible explanation for why older adults, who have lower levels of these hormones, are more susceptible to the severe effects of the virus.
 
Interestingly, neither hormone affected the expression of other receptors involved in immune responses, such as TLR3, which is responsible for detecting viral components. This suggests that testosterone and estradiol specifically target the pathways that lead to hyperinflammation without suppressing the broader immune response needed to fight off the virus.
 
Implications for Treatment and Prevention
The findings from this study could have significant implications for treating and preventing severe COVID-19, especially in older adults and individuals with obesity. Hormone replacement therapies could potentially be explored as a way to reduce inflammation in at-risk groups, although more research is needed to understand the full implications of such treatments.
 
Moreover, the study’s focus on macrophages, a type of immune cell that plays a crucial role in both early and late stages of infection, opens the door to new therapeutic approaches. By targeting the immune system’s inflammatory response rather than the virus itself, these treatments could help prevent the complications that lead to severe illness and death.
 
Conclusion
This study sheds light on the important role that sex hormones, particularly testosterone and estradiol, play in modulating the immune response to COVID-19. By reducing the production of pro-inflammatory cytokines and decreasing the expression of key receptors on macrophages, these hormones may offer a protective effect against the severe inflammation that characterizes the worst cases of COVID-19.
 
However, as people age, their hormone levels naturally decline, leaving older adults and those with obesity more vulnerable to severe disease. The study’s findings suggest that hormone therapies could be a promising avenue for future research and treatment, potentially offering a way to protect these at-risk groups from the most dangerous effects of the virus.
 
The study findings were published in the peer-reviewed European Journal of Immunology.
https://onlinelibrary.wiley.com/doi/10.1002/eji.202451226
 
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